S-aryl cysteines are useful compounds in the biological study of metabolism, and they are useful intermediates in a synthesis of a variety of pharmaceutically active compounds. For example, S-aryl cysteine derivatives (mercapturic acids) are useful for studying the xenobiotics metabolic pathways. L. F. Chasseaud, Drug Metab. Rev., 1973, 2, 185. In addition, chiral S-aryl-L-cysteines have been used successfully to target the human immunodeficient virus (HIV) as a therapy for the treatment of AIDS. Kaldor et al., J. Med. Chem. 1997, 40 (24), 3979-3985.
Many currently available synthetic methods for S-aryl cysteine involve preparation of racemic mixtures. There are, however, a number of disadvantages associated with racemic mixtures of such compound. A racemic mixture of S-aryl cysteine results in production of racemic drugs. It is well known that certain physiological properties of chiral drugs are dependent upon stereochemistry of the drug and the undesired side-effects are often attributed to the presence of the undesired stereoisomer of the chiral drug. Accordingly, a high enantioselective synthesis of a chiral drug will result in a drug having a desired therapeutic activity with a reduced amount of undesired side-effects. Of course, the synthesis of a chiral drug can include a step of separating a racemic mixture; however, this is often time consuming and costly. In addition, racemic synthesis requires discarding one half of the compound unless the undesired isomer can be converted to a desired isomer. Moreover, not all racemic compounds can be resolved to provide a satisfactory yield of a desired enantiomer.
Current methods for enantioselective synthesis of S-aryl cysteine involve enzymatic methods (See, for example, Japanese Patent No. 58,146,287 and European Patent Application No. EP 754,759, which are assigned to Mitsui Toatsu Chemicals, Inc.) and are applicable to preparation of only a limited number of S-aryl cysteines.
Most of the current chemical synthetic methods for enantioselective preparation of S-aryl cysteine result in a racemic mixture, use elaborate reagents dramatically increasing the overall cost, or result in unacceptable levels of enantioselectivity to be useful in a pharmaceutical process.
Recently, Knight and Sibley (D. W. Knight and A. W. Sibley, J. Chem. Soc., Perkin Trans. 1, 1997, 2179-2187) reported that the. displacement of N-benzyloxycarbonyl-O-p-toluenesulfonyl serine methyl ester (or methyl (S)-2-benzyloxycarbonylamino-3-methylsulfonyloxypropanoate) with freshly prepared sodium thiophenylate in DMF at about 0.degree. C. afforded the desired N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (or methyl (R)-2-benzyloxycarbonylamino-3-phenylthiopropanoate) in 98% yield providing a reported optical rotation of [.alpha.].sup.20.sub.D -17.2 (c, 1.8; MeOH). No enantiomeric ratio of the product was reported. Furthermore, the use of sodium phenolate, prepared from sodium hydride, thiophenol and DMF is not amenable to large scale manufacture.
Therefore, there is a need for an efficient, concise and enantioselective method suitable for the large scale manufacture of S-aryl cysteine using relatively inexpensive reagents.